Chemical compounds

ABSTRACT

3-carboxy quinoline derivatives, which are useful as YAK3 inhibitors are described herein. The described invention also includes methods of making such 3-carboxy quinoline derivatives as well as methods of using the same in the treatment of diseases mediated by inappropriate YAK3 activity.

BACKGROUND OF THE INVENTION

The present invention relates to 3-carboxy quinoline derivatives,compositions and medicaments containing the same, as well as processesfor the preparation and use of such compounds, compositions andmedicaments. Such 3-carboxy quinoline derivatives are useful in thetreatment of diseases associated with inappropriate YAK3 activity.

The YAK family of serine/threonine protein kinases, represent a novelfamily of dual specificity protein kinases with unique structural,enzymatic, and probably functional features (Becker and Joost (1999)Prog. Nucl. Acid Res. 62, 1-17). Four members of the YAK family havebeen identified by large scale screening of human cDNA libraries using ayeast YAK1 sequence, and have been termed h (human)Yak1, 2, 3, and 4.(See U.S. Pat. No. 5,972,606 (hYAK1), U.S. Pat. No. 6,001,623 (hYAK2),and U.S. Pat. No. 5,965,420 (hYAK3)) In the yeast S. cerevisiae YAK1functions as a negative regulator of cell growth (Garrett, S., Menold,M. M., and Broach, J. (1991) Mol. Cell Biol. 11, 4045-4051). Deletion ofthe three PKA genes (tpk1, tpk2, and tpk3) in yeast causes cell cyclearrest at G₁ while this growth defect is alleviated by removal of theYAK1 gene (Garrett, S., and Broach, J. (1989) Gene Dev. 3, 1336-1348).Recent data indicates that yYAK1 expression is controlled by twotranscription factors MSN2/4 which are negatively regulated by PKA, thusyYAK1 acts downstream of PKA (Smith, A., Ward, M. P. and Garrett, S.(1998) EMBO J. 17, 3556-3564). While the means by which yYAK1 inhibitscell growth is still not known, overexpression of yYAK1 suppresses cellcycle arrest in late mitotic mutants (cdc15, cdc5, dbf2, and tem1)defective in anaphase-promoting complex (APC) (Jaspersen, S. L Charles,J. F., Tinker-Kulberg, R. L., and Morgan, D. O. (1998) Mol. Biol. of theCell. 9, 2803-2817). Recent work in Dictyostelium has uncovered a yYAK1homolog which is required for the transition from growth to developmentgiving support to the involvement of this family of kinases in cellgrowth (Souza, G. M., Lu, S. and Kuspa, A. (1998) Development 125,

Northern analysis was carried out to determine the distribution of hYAK3mRNA in human tissues. Membranes containing mRNA from multiple humantissues (Clontech #7760-1, #7759-1, and #7768-1) were hybridized to anhYAK3 probe and washed under high stringency conditions as directed.Hybridized mRNA was visualized by exposing the membranes to X-ray film.One major transcript at ˜2.5 kb was present in testis, and transcriptsof 2.5, 8 and 10 kb were present in bone and fetal liver. Thetranscripts were not visible in any other tissues; however, dot blotanalysis using a Human Master blot (Clontech #7770-1) indicated thathYAK3 is expressed in other tissues including skeletal muscle.

Investigations with primary cells and hematopoietic cell lines from bothhuman and mouse indicate that cells of the erythroid lineage maypredominantly account for the elevated hYAK3 expression. These datasuggest that hYAK3 may have a lineage-specific function. In cell lines,hYAK3 is present at higher levels in cells with an erythroid phenotypethan other hematopoietic lineages, including myeloid, monocytic andlymphoid cell lines. This profile is completely distinct from hYAK1,which has been observed only at low constitutive levels in hematopoieticcells and tissues. EPO-treatment of human bone marrow in vitro leads toinduction and sustained expression of hYAK3 message and hYAK3 protein.Splenocytes from mice made anemic by phenylhydrazine treatment becomeenriched in erythroid progenitors and exhibit increased expression ofhYAK3. Increases in both message and protein accompany induction oferythroid differentiation in UT7-EPO cells.

In yeast, yYAK is a negative regulator of growth via the cell cycle.Consequently, we would anticipate that hYAK3 participates in cell cyclecontrol, and/or commitment to differentiation. We predict that anantagonist of hYAK3 would have a positive effect on cell growth. Ourdata indicates that it also may be involved in terminal differentiationand growth arrest in hematopoietic cells, especially in the erythroidlineage.

The present inventors have discovered novel 3-carboxy quinolinecompounds, which are inhibitors of YAK3 activity. Such 3-carboxyquinoline derivatives are useful in the treatment of disordersassociated with inappropriate YAK3 activity, especially diseases of thehematopoietic systems, including anemias due to renal insufficiency orto chronic disease, such as autoimmunity or cancer and drug-inducedanemias, polycythemia, myelodysplastic syndrome, aplastic anemia andmyelosuppression; cytopenia; neurodegeneration; and also for controllingmale fertility, especially for the purpose of achieving contraception.

BRIEF SUMMARY OF THE INVENTION

In one aspect of the present invention, there is provided a compound ofFormula (I):

wherein:

R¹ is —H or C₁-C₆ alkyl;

R² is the group defined by -(Q)_(q)-(Q¹)_(r)-(Q²),

wherein:

Q is CH₂ and q is 0, 1, 2, 3, or 4;

Q¹ is O, NH, or C(H)(R′) where R′ is —OH; and r is 0 or 1, and

Q² is —H, C₁-C₆ alkyl, aryl, heterocyclic, C₃-C₇ cycloalkyl,—C(O)OR^(b), NR^(b)R^(b), or heteroaryl; where Q² is optionallysubstituted with at least one R^(a) group;

R³ and R^(3a) are independently selected from —H, C₁-C₆ alkyl, or C₁-C₆hydroxyalkyl, m is 0 or 1, and n is 0 or 1, or

m is 1 and n is 1 and R³ and R^(3a) together with the atoms to whichthey are attached form the optionally substituted fused ring

R⁴ is —OH, —NHS(O)₂R^(c), or —N(R^(b))R;

R⁵ is —H or halo;

R⁶ is —H, aryl, —OR^(b);

R^(a) is independently selected from C₁-C₆ alkyl, halo, aryl,—C(O)OR^(b), —C(O)R^(d), —OH, —NR^(b)R^(b), —N(H)C(O)OR^(b),—N(H)C(O)N(H)R^(e), —N(H)S(O)₂R^(e), —N(H)S(O)₂NR^(b)R^(b), C₁-C₆alkoxy, C₁-C₆ haloalkyl, —NO₂, —CN, —SF₅, ═O, —S(O)₂NR^(b)R^(b), oraryloxy;

R^(b) is —H, C₁-C₆alkyl, or C₂-C₄alkenyl;

R^(c) is aryl or C₁-C₆ alkyl;

R^(d) is C₁-C₆alkyl, aryl, NR^(b)R^(b), or N(H)(CH₂)_(s)NR^(b)R^(b),

R^(e) is —H, aryl or C₁-C₆alkyl;

s is 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

In a second aspect of the present invention, there is provided apharmaceutical composition comprising a therapeutically effective amountof a compound of formula (I) or a salt, solvate, or a physiologicallyfunctional derivative thereof and one or more of pharmaceuticallyacceptable carriers, diluents and excipients.

In a third aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being mediated byinappropriate YAK3 activity, comprising: administering to said mammal atherapeutically effective amount of a compound of formula (I) or a salt,solvate or a physiologically functional derivative thereof.

In a fourth aspect of the present invention, there is provided acompound of formula (I), or a salt, solvate, or a physiologicallyfunctional derivative thereof for use in therapy.

In a fifth aspect of the present invention, there is provided the use ofa compound of formula (I), or a salt, solvate, or a physiologicallyfunctional derivative thereof in the preparation of a medicament for usein the treatment of a disorder mediated by inappropriate YAK3 activity.

DETAILED DESCRIPTION

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

As used herein the term “alkyl” refers to a straight- or branched-chainhydrocarbon radical having from one to twelve carbon atoms, optionallysubstituted with substituents selected from the group consisting ofC₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl,C₁-C₆ alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aryl, aryloxy, heteroaryl, aminosulfonyloptionally substituted by alkyl, nitro, cyano, halo, or C₁-C₆perfluoroalkyl, multiple degrees of substitution being allowed. Examplesof “alkyl” as used herein include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl,isopentyl, and the like.

As used herein, the term “C₁-C₆ alkyl” refers to an alkyl group, asdefined above, containing at least 1, and at most 6 carbon atoms.Examples of such branched or straight-chained alkyl groups useful in thepresent invention include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, isopentyl,and n-hexyl.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the group whichincludes C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halo, and C₁-C₆ perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, n-propylene,n-butylene, and the like.

As used herein, the terms “C₁-C₃ alkylene” and “C₁-C₆ alkylene” refer toan alkylene group, as defined above, which contains at least 1, and atmost 3 or 6, carbon atoms respectively. Examples of “C₁-C₃ alkylene” and“C₁-C₆ alkylene” groups useful in the present invention include, but arenot limited to, methylene, ethylene, n-propylene, n-butylene,isopentylene, and the like.

As used herein, the term “halogen” refers to fluorine (F), chlorine(Cl), bromine (Br), or iodine (I) and the term “halo” refers to thehalogen radicals: fluoro (—F), chloro (—Cl), bromo(—Br), and iodo(—I).

As used herein, the term “C₁-C₆ haloalkyl” refers to an alkyl group asdefined above containing at least 1, and at most 6 carbon atomssubstituted with at least one halo group, halo being as defined herein.Examples of such branched or straight chained haloalkyl groups useful inthe present invention include, but are not limited to, methyl, ethyl,propyl, isopropyl, isobutyl and n-butyl substituted independently withone or more halos, e.g., fluoro, chloro, bromo and iodo.

As used herein, the term “C₁-C₆ hydroxyalkyl” refers to an alkyl groupas defined above containing at least 1, and at most 6 carbon atomssubstituted with at least one hydroxy group, hydroxy being as definedherein. Examples of such branched or straight chained hydroxyalkylgroups useful in the present invention include, but are not limited to,methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted withone or more hydroxy groups.

As used herein, the term “cycloalkyl” refers to a non-aromatic cyclichydrocarbon ring containing from 3 to 10 carbon atoms and whichoptionally includes a C₁-C₆ alkylene linker through which it may beattached. In a like manner the term “C₃-C₇ cycloalkyl” refers to anon-aromatic cyclic hydrocarbon ring having from three to seven carbonatoms and which optionally includes a C₁-C₆ alkylene linker throughwhich it may be attached. The C₁-C₆ alkylene group is as defined above.Exemplary “C₃-C₇ cycloalkyl” groups useful in the present inventioninclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a three to twelve-membered non-aromatic heterocyclic ring,being saturated or having one or more degrees of unsaturation,containing one or more heteroatom substitutions selected from S, S(O),S(O)₂, O, or N, optionally substituted with substituents selected fromthe group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl,C₁-C₆ alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halo, aryl, aralkyl, heteroaryl, or C₁-C₆ perfluoroalkyl,multiple degrees of substitution being allowed. Such a ring may beoptionally fused to one or more other “heterocyclic” ring(s), cycloalkylring(s), or aryl ring(s). Examples of “heterocyclic” moieties include,but are not limited to, tetrahydrofuranyl such as tetrahydrofuran-2-yl,pyranyl, 1,4-dioxanyl, 1,3-dioxanyl, piperidinyl such as piperdin-1-yl,piperazinyl such as 4-tert-butoxycarbonyl-piperazin-1-yl,2,4-piperazinedionyl, pyrrolidinyl such as 2-oxo-pyrrolidin-1-yl andpyrrolidin-2-yl, imidazolidinyl such as 2-oxo-imidazolidin-1-yl,pyrazolidinyl, morpholinyl such as morpholin-4-yl, thiomorpholinyl,tetrahydrothiopyranyl, tetra hydrothiophenyl, benzodioxyl such as benzo[1,3]dioxol-5-yl, and the like as well as additional substitutedversions thereof.

As used herein, the term “aryl” refers to an optionally substitutedbenzene ring or to an optionally substituted benzene ring system fusedto one or more optionally substituted benzene or cycloalkyl rings toform, for example, anthracene, phenanthrene, indan, or napthalene ringsystems. Exemplary optional substituents include C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆alkylsulfenyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylsulfonylamino,arylsulfonoamino, alkylcarboxy, alkylcarboxyamide, oxo, hydroxy,mercapto, amino optionally substituted by alkyl or acyl, carboxy,tetrazolyl, carbamoyl optionally substituted by alkyl, aryl, orheteroaryl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl,aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halo, heteroaryl, heterocyclyl, aryloptionally substituted with aryl, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, orC₁-C₆ alkylsulfonyl, ureido, arylurea, alkylurea, cycloalkylurea,alkylthiourea, aryloxy, or aralkoxy, multiple degrees of substitutionbeing allowed. Examples of “aryl” groups include, but are not limitedto, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, indanyl,tetrahydronaphthylenyl, as well as substituted derivatives thereof.

As used herein, the term “aralkyl” refers to an aryl or heteroarylgroup, as defined herein, attached through a C₁-C₃ alkylene linker,wherein the C₁-C₃ alkylene is as defined herein. Examples of “aralkyl”include, but are not limited to, benzyl, phenylpropyl, phenylethyl,2-pyridylmethyl, 3-isoxazolylmethyl, 5-methyl-3-isoxazolylmethyl, and2-imidazolyl ethyl.

As used herein, the term “heteroaryl” refers to a monocyclic five toseven membered aromatic ring, or to a fused bicyclic or tricyclicaromatic ring system comprising two of such monocyclic five to sevenmembered aromatic rings. These heteroaryl rings contain one or morenitrogen, sulfur, and/or oxygen heteroatoms, where N-oxides and sulfuroxides and dioxides are permissible heteroatom substitutions and may beoptionally substituted with up to three members selected from a groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, tetrazolyl, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halo, C₁-C₆ perfluoroalkyl, heteroaryl, oraryl, multiple degrees of substitution being allowed. Examples of“heteroaryl” groups used herein include, but are not limited to,furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl,thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl,quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl,indazolyl, and substituted versions thereof.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is alkyl as defined above and the term “C₁-C₆alkoxy” refers to analkoxy group as defined herein wherein the alkyl moiety contains atleast 1, and at most 6, carbon atoms. Exemplary C₁-C₆ alkoxy” groupsuseful in the present invention include, but are not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.

As used herein, the term “amino” refers to the group —NH₂.

As used herein the term “alkylamino” refers to the group —NHR_(a)wherein R_(a) is alkyl as defined above.

As used herein the term “arylamino” refers to the group —NHR_(a) whereinR_(a) is aryl as defined above.

As used herein the term “aralkylamino” refers to the group —NHR_(a)wherein R_(a) is an aralkyl group as defined above.

As used herein the term “aralkoxy” refers to the group R_(b)R_(a)O—,where R_(a) is alkylene and R_(b) is aryl or heteroaryl all as definedabove.

As used herein the term “aryloxy” refers to the group R_(a)O—, whereR_(a) is aryl or heteroaryl both as defined above.

As used herein the term “ureido” refers to the group —NHC(O)NH₂

As used herein, the term “arylurea” refers to the group —NHC(O)NHR_(a)wherein R_(a) is aryl as defined above.

As used herein, the term “arylthiourea” refers to the group—NHC(S)NHR_(a) wherein R_(a) is aryl as defined above.

As used herein, the term “alkylurea” refers to the group —NHC(O)NHR_(a)wherein R_(a) is alkyl as defined above.

As used herein, the term “cycloalkylurea” refers to the group—NHC(O)NHR_(a) wherein R_(a) is cycloalkyl as defined above.

As used herein, the term “C₃-C₇ cycloalkoxy” refers to the groupR_(a)O—, where R_(a) is C₃-C₇ cycloalkyl as defined above. ExemplaryC₃-C₇ cycloalkoxy groups useful in the present invention include, butare not limited to, cyclobutoxy, and cyclopentoxy.

As used herein, the term “haloalkoxy” refers to the group R_(a)O—, whereR_(a) is haloalkyl as defined above and the term “C₁-C₆ haloalkoxy”refers to a haloalkoxy group as defined herein wherein the haloalkylmoiety contains at least 1, and at most 6, carbon atoms. Exemplary C₁-C₆haloalkoxy groups useful in the present invention include, but is notlimited to, trifluoromethoxy.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkyl as defined above and the term “C₁-C₆ alkylsulfanyl”refers to an alkylsulfanyl group as defined herein wherein the alkylmoiety contains at least 1, and at most 6, carbon atoms.

As used herein, the term “haloalkylsulfanyl” refers to the groupR_(a)S—, where R_(a) is haloalkyl as defined above and the term “C₁-C₆haloalkylsulfanyl” refers to a haloalkylsulfanyl group as defined hereinwherein the alkyl moiety contains at least 1, and at most 6, carbonatoms.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R_(a) is alkyl as defined above and the term “C₁-C₆ alkylsulfenyl”refers to an alkylsulfenyl group as defined herein wherein the alkylmoiety contains at least 1, and at most 6, carbon atoms.

As used herein, the term “alkylsulfonyl” refers to the groupR_(a)S(O)₂—, where R_(a) is alkyl as defined above and the term “C₁-C₆alkylsulfonyl” refers to an alkylsulfonyl group as defined hereinwherein the alkyl moiety contains at least 1, and at most 6, carbonatoms.

As used herein, the term “alkylsulfonylamino” refers to the group—NHS(O)₂R_(a) wherein R_(a) is alkyl as defined above and the term“C₁-C₆ alkylsulfonylamino” refers to an alkylsulfonylamino group asdefined herein wherein the alkyl moiety contains at least 1, and at most6, carbon atoms.

As used herein, the term “arylsulfonylamino” refers to the group—NHS(O)₂R_(a) wherein R_(a) is aryl as defined above.

As used herein, the term “alkylcarboxyamide” refers to the group—NHC(O)R_(a) wherein R_(a) is alkyl, amino, or amino substituted withalkyl, aryl or heteroaryl as described above.

As used herein the term “alkylcarboxy” refers to the group —C(O)R_(a)wherein R_(a) is alkyl as described above.

As used herein the term “hydroxy” refers to the group —OH.

As used herein, the term “oxo” refers to the group ═O.

As used herein, the term “mercapto” refers to the group —SH.

As used herein, the term “carboxy” refers to the group —C(O)OR_(a),wherein R_(a) is H or alkyl as defined herein.

As used herein, the term “cyano” refers to the group —CN.

As used herein the term “cyanoalkyl” refers to the group —R_(a)CNwherein R_(a) is alkyl as defined above. Exemplary “cyanoalkyl” groupsuseful in the present invention include, but are not limited to,cyanomethyl, cyanoethyl, and cyanoisopropyl.

As used herein, the term “aminosulfonyl” refers to the group —S(O)₂NH₂.

As used herein, the term “carbamoyl” refers to the group —OC(O)NHR_(a),where R_(a) is hydrogen or alkyl as defined herein.

As used herein, the term “carboxamide” refers to the group —C(O)NH₂.

As used herein, the term “sulfanyl” shall refer to the group —S—.

As used herein, the term “sulfenyl” shall refer to the group —S(O)—.

As used herein, the term “sulfonyl” shall refer to the group —S(O)₂— or—SO₂—.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR_(a) is aryl as defined herein.

As used herein, the term “aroylamino” refers to the group R_(a)C(O)NH—,where R_(a) is aryl as defined herein.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—where R_(a) is heteroaryl as defined herein.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is alkyl as defined herein.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—,where R_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl as defined herein.

As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl as defined herein.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s),which occur, and events that do not occur.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide, which uponadministration to a mammal is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. Such derivatives are clear to those skilled in the art, withoutundue experimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or a salt or physiologically functional derivative thereof)and a solvent. Such solvents for the purpose of the invention may notinterfere with the biological activity of the solute. Examples ofsuitable solvents include, but are not limited to, water, methanol,ethanol and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Examples of suitablepharmaceutically acceptable solvents include, without limitation, water,ethanol and acetic acid. Most preferably the solvent used is water.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

Certain of the compounds described herein may contain one or more chiralatoms, or may otherwise be capable of existing as two enantiomers. Thecompounds of this invention include mixtures of enantiomers as well aspurified enantiomers or enantiomerically enriched mixtures. Alsoincluded within the scope of the invention are the individual isomers ofthe compounds represented by formula (I) above as well as any wholly orpartially equilibrated mixtures thereof. The present invention alsocovers the individual isomers of the compounds represented by theformulas above as mixtures with isomers thereof in which one or morechiral centers are inverted. Also, it is understood that any tautomersand mixtures of tautomers of the compounds of formula (I) are includedwithin the scope of the compounds of formula (1).

It is understood that due to the presence of the double bond containingalkenylene chain in formula (I), also included within the scope offormula (I) are the respective pure E and Z geometric isomers as well asmixtures of E and Z isomers of the compounds of formula (I). Theinvention as described and claimed does not set any limiting ratios onprevalence of Z to E isomers.

In one embodiment, the compounds of formula (I) are in the form of asubstantially pure E geometric isomer. In another embodiment, thecompounds of formula (I) are in the form of a substantially pure Zgeometric isomer. In a further embodiment, the compounds of formula (I)are in the form of a mixture of E geometric isomer and Z geometricisomer in any proportions of said geometric isomers.

It is to be understood that reference to compounds of formula (I) above,following herein, refers to compounds within the scope of formula (I) asdefined above with respect to R¹, R², R³, R^(3a), R⁴, R⁵, R, R_(a),R_(b), R^(c), R^(d), R^(e), q, r, s, Q, Q¹, and Q² unless specificallylimited otherwise.

In one embodiment, R¹ is —H or methyl, preferably R¹ is —H.

As indicated above, R² is a group defined by -(Q)_(q)-(Q¹)_(r)-(Q²). Inone embodiment, q and r are 0, and R² is -(Q²). In another embodiment, qis 1, 2, 3, or 4, r is 0 and R² is -(Q)_(q)-(Q²). In another embodiment,q is 0, r is 1, and R² is -(Q¹)-(Q²). In another embodiment, q is 1, 2,3, or 4 and r are 1, and R² is -(Q)_(q)-(Q¹)-(Q²).

In one embodiment, q is 1, 2, 3, or 4 and Q is CH₂. In anotherembodiment, m is 1, 2, or 3 and Q is CH₂. In a preferred embodiment, qis 1 or 2 and Q is CH₂.

In one embodiment, r is 0 or 1 and Q¹ is NH or O. In another embodiment,r is 0 or 1 and Q¹ is NH. In a preferred embodiment, r is 0.

In one embodiment, Q² is C₁-C₆ alkyl, aryl, heterocyclic, C₃-C₇cycloalkyl, or heteroaryl each optionally substituted with at least oneR^(a) group, wherein R^(a) is as defined above. In another embodiment,Q² is aryl optionally substituted with at least one R^(a) group, whereinR^(a) is as defined above.

In one embodiment, R² is a group defined by -(Q)_(q)-(Q¹)_(r)-(Q²),where Q is CH², q is 1, 2, 3, or 4, r is 0, and Q² is aryl optionallysubstituted with at least one R^(a) group, wherein R^(a) is as definedabove, preferably Q is CH², q is 1, 2, or 3, r is 0, and Q² is phenyloptionally substituted with at least one R^(a) group, wherein R^(a) isas defined above, more preferably Q is CH², q is 2, r is 0, and Q² isphenyl optionally substituted with at least one R^(a) group, whereinR^(a) is as defined above.

In another embodiment, R² is a group defined by -(Q)_(q)-(Q¹)_(r)-(Q²),where q is 0, r is 0, and Q² is aryl optionally substituted with atleast one R^(a) group, wherein R^(a) is as defined above, preferably qis 0, r is 0, and Q² is phenyl optionally substituted with at least oneR^(a) group, wherein R^(a) is as defined above.

In another embodiment, R² is a group defined by -(Q)_(q)-(Q¹)_(r)-(Q²),where q is 0, r is 0, and Q² is C₁-C₆ alkyl optionally substituted withat least one R^(a) group, wherein R^(a) is as defined above.

In one embodiment, m is 0, n is 1, and R³ is —H or C₁-C₆alkyl,preferably m is 0, n is 1, and R³ is —H or methyl. In an alternativeembodiment, m is 1, n is 0, and R^(3a) is —H or C₁-C₆alkyl, preferably mis 1, n is 0, and R³′ is —H or methyl.

In another embodiment, m is 1 and n is 1 and R³ and R^(3a) together withthe atoms to which they are attached form the optionally substitutedfused ring

It will be understood by those skilled in the art that the range ofoptional substituents will vary according to, which R³ and R^(3a) groupsform the fuse ring.

In one embodiment, R⁴ is —NHS(O)₂R^(c), wherein R^(c) is aryl or C₁-C₆alkyl, preferably R^(c) is phenyl, substituted phenyl or methyl. In apreferred embodiment, R⁴ is —OH. In another embodiment, R⁴ is —N(R^(b))Rwherein R is —H, aryl or —OR^(b) and R^(b) is —H, C₁-C₆alkyl, orC₁-C₆alkenyl.

In one embodiment, R⁵ is halo, preferably —Br. In a preferred embodimentR⁵ is —H.

Specific examples of compounds of the present invention include thefollowing:

-   2-(3-tert-butoxycarbonylamino-propylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(3-amino-propylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-(4-tert-butoxycarbonylamino-butyl    amino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(2-tert-butoxycarbonylamino-ethyl    amino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(3-dimethylamino-propylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(2-dimethylamino-ethylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(2-amino-ethylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(4-amino-butylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-benzylamino-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-phenethylamino-quinoline-3-carboxylic acid;-   7-methoxy-2-(2-pyridin-4-yl-ethylamino)-quinoline-3-carboxylic acid;-   2-(2-dimethylamino-ethylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(indan-2-ylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-(3-morpholin-4-yl-propylamino)-quinoline-3-carboxylic    acid;-   2-(3-diethylamino-propylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-quinoline-3-carboxylic    acid;-   2-(4-tert-butyl-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-quinoline-3-carboxylic    acid;-   2-(4-dimethylamino-benzylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-(2-morpholin-4-yl-ethylamino)-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(4-phenoxy-phenyl)-ethylamino]-quinoline-3-carboxylic    acid;-   2-cyclohexylamino-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-[(tetra hydro-fu ran-2-yl    methyl)-amino]-quinoline-3-carboxylic acid;-   2-(2-hydroxy-ethylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(2-hydroxy-2-phenyl-ethylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-[2-(3-bromo-4-methoxy-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-(4-methyl-benzylamino)-quinoline-3-carboxylic acid;-   7-methoxy-2-(2-pyridin-3-yl-ethylamino)-quinoline-3-carboxylic acid;-   2-[2-(3,4-dimethoxy-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-benzylamino-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-piperidin-1-yl-quinoline-3-carboxylic acid;-   7-methoxy-2-(3-pentafluorosulfanyl-phenylamino)-quinoline-3-carboxylic    acid;-   7-methoxy-2-(5,6,7,8-tetrahydro-naphthalen-1-ylamino)-quinoline-3-carboxylic    acid;-   7-methoxy-2-(naphthalen-1-ylamino)-quinoline-3-carboxylic acid;-   2-[4-(2-diethylamino-ethylcarbamoyl)-phenylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-(3-tert-butoxycarbonylamino-benzylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(4-tert-butoxycarbonylamino-benzylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(4-amino-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-(2,4,6-trimethoxy-benzylamino)-quinoline-3-carboxylic    acid;-   7-methoxy-2-[3-(3-phenyl-ureido)-benzylamino]-quinoline-3-carboxylic    acid;-   7-methoxy-2-[4-(3-phenyl-ureido)-benzylamino]-quinoline-3-carboxylic    acid;-   7-methoxy-2-[4-(toluene-4-sulfonylamino)-benzylamino]-quinoline-3-carboxylic    acid;-   7-methoxy-2-(3-ureido-benzylamino)-quinoline-3-carboxylic acid;-   2-(dimethylaminosulfonylamino-benzylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(4-methoxy-phenyl)-ethylamino]-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(2-methoxy-phenyl)-ethylamino]-quinoline-3-carboxylic    acid;-   7-methoxy-2-(4-methoxy-benzylamino)-quinoline-3-carboxylic acid;-   2-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-(3-trifluoromethyl-benzylamino)-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(4-nitro-phenyl)-ethylamino]-quinoline-3-carboxylic    acid;-   2-(3-imidazol-1-yl-propylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-(4-sulfamoyl-benzylamino)-quinoline-3-carboxylic acid;-   7-methoxy-2-(3-methoxy-benzylamino)-quinoline-3-carboxylic acid;-   2-(2-chloro-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-[2-(3-fluoro-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-[2-(4-amino-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-(3-amino-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(2-benzo[1,3]dioxol-5-yl-ethylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(3-methoxy-phenyl)-ethylamino]-quinoline-3-carboxylic    acid;-   2-[2-(3-chloro-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(4-sulfamoyl-phenyl)-ethylamino-quinoline-3-carboxylic    acid;-   2-[2-(2-chloro-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-[2-(4-hydroxy-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-(3-bromo-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(3-chloro-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-(2-piperazin-1-yl-ethylamino)-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-quinoline-3-carboxylic    acid;-   7-methoxy-2-piperidin-1-yl-quinoline-3-carboxylic acid;-   2-(4-chloro-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(4-hydroxy-piperidin-1-yl)-7-methoxy-quinoline-3-carboxylic acid;-   2-(tert-butoxycarbonylmethyl-amino)    -7-methoxy-quinoline-3-carboxylic acid;-   2-[2-(2-hydroxy-ethoxy)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-(3-methoxy-propylamino)-quinoline-3-carboxylic acid;-   7-methoxy-2-(2-methoxy-ethylamino)-quinoline-3-carboxylic acid;-   2-(3-hydroxy-propylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(2-carboxy-ethylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-propylamino-quinoline-3-carboxylic acid;-   2-(carboxymethyl-amino)-7-methoxy-quinoline-3-carboxylic acid;-   3-(2-chloro-phenylamino)-6-methoxy-naphthalene-2-carboxylic acid;-   2-(2-chloro-phenylamino)-7-methoxy-quinoline-3-carboxylic acid    phenylamide;-   2-(2-chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acid    phenylamide;-   2-(2-chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acid;-   2-(2-chloro-phenylamino)-7-(2-hydroxy-ethoxy)-quinoline-3-carboxylic    acid;-   2-(3,4-dichlorophenylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(3-biphenylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-(phenylamino)-quinoline-3-carboxylic acid;-   7-methoxy-2-(methyl-3-methylphenylamino)-quinoline-3-carboxylic    acid;-   2-(cyclohexylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(3-chlorophenylamino)-6,7-dimethoxy-quinoline-3-carboxylic acid;-   2-(3-chlorophenylamino)-6,7-methylenedioxy-quinoline-3-carboxylic    acid;-   2-(3-chlorophenylamino)-7-hydroxy-quinoline-3-carboxylic acid;-   8-bromo-2-(3-chlorophenylamino)-7-hydroxy-quinoline-3-carboxylic    acid;-   2-(3-chlorophenylamino)-7-methoxy-quinoline-3-carboxamide    phenylsulphonamide;-   2-(3-chlorophenylamino)-7-methoxy-quinoline-3-carboxamide    2-nitro-phenylsulphonamide;-   2-(3-chlorophenylamino)-7-methoxy-quinoline-3-carboxamide    methylsulphonamide;-   8-bromo-2-(3-chlorophenylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(3-acetophenylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(2-benzophenone-yl-amino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(2-fluoro-5-methylphenylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(2-cyanophenylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(2-chloro-6-methylphenylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(4-carboxybenzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(3-chloro-6-methoxyphenylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(2-ethylphenylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-(4-nitrophenylamino)-quinoline-3-carboxylic acid;-   2-(4-carboxamidophenylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-(4-hydroxyphenethylamino)-quinoline-3-carboxylic acid;    and-   7-methoxy-2-(piperidin-4-ol)-quinoline-3-carboxylic acid;    or a salt, solvate, or physiologically functional derivative    thereof.

Further specific examples of compounds of the present invention includethe following:

or a salt, solvate, or physiologically functional derivative thereof.

Typically, the salts of the present invention are pharmaceuticallyacceptable salts. Salts encompassed within the term “pharmaceuticallyacceptable salts” refer to non-toxic salts of the compounds of thisinvention. Salts of the compounds of the present invention may compriseacid addition salts derived from a nitrogen on a substituent in thecompound of formula (I). Representative salts include the followingsalts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, monopotassium maleate,mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate(embonate), palmitate, pantothenate, phosphateldiphosphate,polygalacturonate, potassium, salicylate, sodium, stearate, subacetate,succinate, tannate, tartrate, teoclate, tosylate, triethiodide,trimethylammonium and valerate. Other salts, which are notpharmaceutically acceptable, may be useful in the preparation ofcompounds of this invention and these form a further aspect of theinvention.

While it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I), as well as salts, solvates andphysiological functional derivatives thereof, may be administered as theraw chemical, it is possible to present the active ingredient as apharmaceutical composition. Accordingly, the invention further providespharmaceutical compositions, which include therapeutically effectiveamounts of compounds of the formula (I) and salts, solvates andphysiological functional derivatives thereof, and one or morepharmaceutically acceptable carriers, diluents, or excipients. Thecompounds of the formula (I) and salts, solvates and physiologicalfunctional derivatives thereof, are as described above. The carrier(s),diluent(s) or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. In accordance with another aspectof the invention there is also provided a process for the preparation ofa pharmaceutical formulation including admixing a compound of theformula (I), or salts, solvates and physiological functional derivativesthereof, with one or more pharmaceutically acceptable carriers, diluentsor excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I),depending on the condition being treated, the route of administrationand the age, weight and condition of the patient, or pharmaceuticalformulations may be presented in unit dose forms containing apredetermined amount of active ingredient per unit dose. Preferred unitdosage formulations are those containing a daily dose or sub-dose, asherein above recited, or an appropriate fraction thereof, of an activeingredient. Furthermore, such pharmaceutical formulations may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I), and salts, solvates and physiologicalfunctional derivatives thereof, can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of formula (I) and salts, solvates and physiologicalfunctional derivatives thereof may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, orpolyethyleneoxidepolylysine substituted with palmitoyl residues.Furthermore, the compounds may be coupled to a class of biodegradablepolymers useful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the animal, the precise condition requiringtreatment and its severity, the nature of the formulation, and the routeof administration, and will ultimately be at the discretion of theattendant physician or veterinarian. However, an effective amount of acompound of formula (I) for the treatment of neoplastic growth, forexample colon or breast carcinoma, will generally be in the range of 0.1to 100 mg/kg body weight of recipient (mammal) per day and more usuallyin the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kgadult mammal, the actual amount per day would usually be from 70 to 700mg and this amount may be given in a single dose per day or more usuallyin a number (such as two, three, four, five or six) of sub-doses per daysuch that the total daily dose is the same. An effective amount of asalt or solvate, or physiologically functional derivative thereof, maybe determined as a proportion of the effective amount of the compound offormula (I) per se. It is envisaged that similar dosages would beappropriate for treatment of the other conditions referred to above.

The compounds of formula (I) and salts, solvates and physiologicalfunctional derivatives thereof, are believed to have utility in treatingconditions of hematopoietic cellular deficiency, such as anemias,including anemias due to renal insufficiency or to chronic disease, suchas autoimmunity or cancer, neutropenia, cytopenia, drug-induced anemias,polycythemia, cancer and myelosuppression as a result of inhibition ofthe protein kinase YAK3.

The present invention thus also provides compounds of formula (I) andpharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof, for use in medicaltherapy, and particularly in the treatment of disorders mediated by YAK3activity.

The inappropriate YAK3 activity referred to herein is any YAK3 activitythat deviates from the normal YAK3 activity expected in a particularmammalian subject. Inappropriate YAK3 activity may take the form of, forinstance, an abnormal increase in activity, or an aberration in thetiming and or control of YAK3 activity. Such inappropriate activity mayresult then, for example, from overexpression or mutation of the proteinkinase leading to inappropriate or uncontrolled activation.

The present invention is directed to methods of regulating, modulating,or inhibiting YAK3 for the prevention and/or treatment of disordersrelated to unregulated YAK3 activity. In particular, the compounds ofthe present invention can also be used in the treatment of certain formsof hematopoietic cellular deficiency, such as anemias, including anemiasdue to renal insufficiency or to chronic disease, such as autoimmunityor cancer, neutropenia, cytopenia, drug-induced anemias, polycythemia,cancer and myelosuppression.

A further aspect of the invention provides a method of treatment of amammal suffering from a disorder mediated by YAK3 activity, whichincludes administering to said subject an effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt, solvate, or aphysiologically functional derivative thereof.

A further aspect of the present invention provides the use of a compoundof formula (1), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of a disordercharacterized by inappropriate YAK3 activity.

Certain embodiments of the present invention will now be illustrated byway of example only. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds.

EXAMPLES

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

g (grams); mg (milligrams);

L (liters); mL (milliliters);

μL (microliters); psi (pounds per square inch);

M (molar); mM (millimolar);

i. v. (intravenous); Hz (Hertz);

MHz (megahertz); mol (moles);

mmol (millimoles); rt (room temperature);

min (minutes); h (hours);

mp (melting point); TLC (thin layer chromatography);

T_(r) (retention time); RP (reverse phase);

MeOH (methanol); i-PrOH (isopropanol);

TEA (triethylamine); TFA (trifluoroacetic acid);

TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran);

DMSO (dimethylsulfoxide); AcOEt (ethyl acetate);

DME (1,2-dimethoxyethane); DCM (dichloromethane);

DCE (dichloroethane); DMF (N,N-dimethylformamide);

DMPU (N,N′-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole);

IBCF (isobutyl chloroformate); HOAc (acetic acid);

HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole);

mCPBA (meta-chloroperbenzoic acid;

EDC (1-[3-dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride);

BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl);

DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl);

Ac (acetyl); atm (atmosphere);

TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl);

TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl);

DMAP (4-dimethylaminopyridine); BSA (bovine serum albumin)

ATP (adenosine triphosphate); HRP (horseradish peroxidase);

DMEM (Dulbecco's modified Eagle medium);

HPLC (high pressure liquid chromatography);

BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride);

TBAF (tetra-n-butylammonium fluoride);

HBTU(O-Benzotriazole-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate).

HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid);

DPPA (diphenylphosphoryl azide);

fHNO₃ (fuming HNO₃); and

EDTA (ethylenediaminetetraacetic acid).

All references to ether are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at room temperature unlessotherwise noted.

¹H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity-400 instrument, a Brucker AVANCE-400, or a General ElectricQE-300. Chemical shifts are expressed in parts per million (ppm, δunits). Coupling constants are in units of hertz (Hz). Splittingpatterns describe apparent multiplicities and are designated as s(singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m(multiplet), br (broad).

HPLC were recorded on a Gilson HPLC or Shimazu HPLC system by thefollowing conditions. Column: 50×4.6 mm (id) stainless steel packed with5 μm Phenomenex Luna C-18; Flow rate: 2.0 mL/min; Mobile phase: Aphase=50 mM ammonium acetate (pH 7.4), B phase=acetonitrile, 0-0.5 min(A: 100%, B: 0%), 0.5-3.0 min (A:100-0%, B:0-100%), 3.0-3.5 min (A: 0%,B: 100%), 3.5-3.7 min (A: 0-100%, B: 100-0%), 3.7-4.5 min (A: 100%, B:0%); Detection: UV 254 nm; Injection volume: 3 μL.

Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA,JOEL SX-102, or a SCIEX-APliii spectrometer; LC-MS were recorded on amicromass 2MD and Waters 2690; high resolution MS were obtained using aJOEL SX-102A spectrometer. All mass spectra were taken underelectrospray ionization (ESI), chemical ionization (CI), electron impact(EI) or by fast atom bombardment (FAB) methods. Infrared (IR) spectrawere obtained on a Nicolet 510 FT-IR spectrometer using a 1-mm NaClcell. Most of the reactions were monitored by thin-layer chromatographyon 0.25 mm E. Merck silica gel plates (60F-254), visualized with UVlight, 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution.Flash column chromatography was performed on silica gel (230-400 mesh,Merck).

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the WorkingExamples.

Compounds of general formula (I) may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1991) ProtectingGroups in Organic Synthesis, John Wiley Et Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprocesses as well as the reaction conditions and order of theirexecution shall be consistent with the preparation of compounds ofFormula (I). Those skilled in the art will recognize if a stereocenterexists in compounds of Formula (I). Accordingly, the present inventionincludes both possible stereoisomers and includes not only racemiccompounds but the individual enantiomers as well. When a compound isdesired as a single enantiomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be effected by any suitable method known in theart. See, for example, Stereochemistry of Organic Compounds by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

Compounds of Formula I can be prepared according to the syntheticsequences illustrated in Schemes 1, 2, 3, 4, and 5 and further detailedin the Examples section following. In general, the synthetic methodsused herein are those detailed in J. C. S. Perkin 1, 1981, 5, 1520-30and J. Het. Chem. 1991, 28(5), 1339-40 for preparing substituted carboxyquinolines.

Scheme 1 illustrates a synthetic scheme for the preparation of a3-carboxyquinoline intermediate useful in the preparation of thecompounds of Formula I. Briefly, a substituted aniline (I) is acylatedwith acetyl chloride in the presence of diethylamine and THF to give theresulting acetanilide (II). Treatment of the acetanilide (II) with POCl₃in DMF gives a 2-chloride-3-formyl quinoline (III). Oxidation with AgNO₃in basic ethanol gives the corresponding 2-chloride-3-carboxy quinoline(IV).

Compounds of Formula (I) having an alkylamine substituent at position R²may be prepared according to the procedures of Schemes 1 and 2 andExamples 1 and 2.

Example 12-(3-tert-butoxycarbonylamino-propylamino)-7-methoxy-quinoline-3-carboxylicacid

A suspension of 2-Chloro-7-methoxy-quinoline-3-carboxylic acid (60 mg,0.22 mmol), (3-Amino-propyl)-carbamic acid tert-butyl ester (77 mg, 0.44mmol), Potassium carbonate (73 mg, 0.46 mmol), and Molecular sieve-4A(300 mg) in dry DMSO (4 ml) was heated at 100° C. for over night. Thereaction mixture was purified by chromatography on SCX column using MeOHas eluent and2-(3-tert-Butoxycarbonylamino-propylamino)-7-methoxy-quinoline-3-carboxylicacid was obtained as white solid after recrystallization from CH₂Cl₂ andHexane; 70 mg (85%). ¹H NMR (400 MHz, DMSO-d₆) ppm 1.38 (s, 9H), 1.73(m, 2H), 3.02 (q, 2H, J=6.1 Hz), 3.53 (q, 2H, J=6.1 Hz), 3.87 (s, 3H),6.84 (dd, 1H, J=2.3, 8.8 Hz), 6.93 (br, 1H), 7.71 (d, 1H, J=8.8 Hz),8.23 (br, 1H), 8.62 (br, 1H), 13.22 (br, 1H). LC/MS: m/z 376 (M+1)⁺, 374(M−1)⁻.

Example 2 2-(3-amino-propylamino)-7-methoxy-quinoline-3-carboxylic acid

A suspension of2-(3-tert-Butoxycarbonylamino-propylamino)-7-methoxy-quinoline-3-carboxylicacid (30 mg, 0.08 mmol) in dry 4N HCl/1,4-Dioxane (1 ml) solution washeated at reflux for 5 days. After evaporating the solvent, the residuewas recrystallized from methanol and diethyl ether to give2-(3-Amino-propylamino)-7-methoxy-quinoline-3-carboxylic acid as thewhite crystal; 19.3 mg (88%). ¹H NMR (400 MHz, DMSO-d₆) ppm 1.91 (m,2H), 2.90 (t, 2H, J=7.3 Hz), 3.56 (m, 2H), 3.83 (s, 3H), 6.74 (dd, 1H,J=2.4, 8.6 Hz), 6.88 (d, 1H, J=2.4 Hz), 7.55 (d, 1H, J=8.6 Hz), 8.24(br, 1H), 8.37 (s, 1H), 10.38 (br, 1H). LC/MS: m/z 276 (M+1)⁺, 274(M−1)⁻.

Additional compounds of formula (I) having an alkylamine R² substituentor tert-butoxycarbonyl derivative thereof were prepared according to theprocedures of Schemes 1 and 2 and Examples 1 and 2 and werecharacterized as being the following.

-   2-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-(4-tert-butoxycarbonylamino-butyl    amino)-7-methoxy-quinoline-3-carboxylic acid; and-   2-(2-tert-butoxycarbonylamino-ethyl    amino)-7-methoxy-quinoline-3-carboxylic acid,-   2-(2-amino-ethylamino)-7-methoxy-quinoline-3-carboxylic acid; and-   2-(4-amino-butylamino)-7-methoxy-quinoline-3-carboxylic acid.

Compounds of Formula (I) having a phenethyl, benzyl, other arylalkyls,heterocyclyl, cycloalkyl, alkylamines or heteroaryl substituent atposition R² may be prepared according to the procedures of Scheme 3 andExamples 3-8. Typically, a suspension of2-Chloro-7-methoxy-quinoline-3-carboxylic acid (60 mg, 0.22 mmol), thecorresponding amine (0.44 mmol), potassium carbonate (73 mg, 0.46 mmol),and molecular sieve-4A (300 mg) in dry DMSO (4 ml) was heated at 100° C.overnight. The reaction mixture was purified by chromatography on SCXcolumn using MeOH as eluent. The corresponding product was obtainedusually as white solid after recrystallization from CH₂Cl₂ and Hexanewith good yield. Examples 3-8 as well as the other specifically namedcompounds were prepared according to the procedures of Schemes 1 and 3.

Example 3 2-benzylamino-7-methoxy-quinoline-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) ppm 3.87 (s, 3H), 4.79 (d, 2H, J=5.0 Hz), 6.86(dd, 1H. J=2.5, 8.6 Hz), 6.92 (d, 1H, J=2.5 Hz), 7.25 (t, 1H, J=7.1 Hz),7.32˜7.42 (m, 4H), 7.74 (d, 1H, J=8.8 Hz), 8.58 (br, 1H), 8.67 (s, 1H).LC/MS: m/z 309 (M+1)⁺, 307 (M−1)⁻.

Example 4 7-methoxy-2-phenethylamino-quinoline-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) ppm 2.95 (t, 2H, J=7.0 Hz), 3.76 (dt, 2H,J=5.3, 7.0 Hz), 3.88 (s, 3H), 6.85 (dd, 1H, J=2.3, 8.8 Hz), 6.96 (s,1H), 7.21 (m, 1H), 7.24˜7.33 (m, 4H), 7.71 (d, 1H, J=8.8 Hz), 8.27 (br,1H), 8.62 (s, 1H). LC/MS: m/z 323 (M+1)⁺, 321 (M−1)⁻.

Example 5 7-methoxy-2-(2-pyridin-4-yl-ethylamino)-quinoline-3-carboxylicacid

¹H NMR (400 MHz, DMSO-d₆) ppm 2.98 (t, 2H, J=7.0 Hz), 3.81 (m, 2H), 3.89(s, 3H), 6.85 (dd, 1H, J=2.0, 8.6 Hz), 6.96 (s, 1H), 7.33 (d, 2H, J=4.6Hz), 7.70 (d, 1H, J=8.6 Hz), 8.33(br, 1H), 8.48(d, 2H, J=4.6 Hz), 8.62(s, 1H), 13.23 (br, 1H). LC/MS: m/z 324 (M+1)⁺, 322 (M−1)⁻.

Example 62-(2-dimethylamino-ethylamino)-7-methoxy-quinoline-3-carboxylic acidhydrochloride

¹H NMR (400 MHz, DMSO-d₆, 333K) ppm 2.88 (s, 6H), 3.41 (t, 2H, J=6.1Hz), 3.91 (s, 3H), 4.05 (br, 2H), 6.98 (dd, 1H, J=2.3, 8.8 Hz), 7.32(br, 1H), 7.82 (d, 1H, J=8.8 Hz), 8.77 (s, 1H). LC/MS: m/z 290 (M+1)⁺,288 (M−1)⁻.

Example 7 2-(indan-2-ylamino)-7-methoxy-quinoline-3-carboxylic acid

1H NMR (400 MHz, DMSO-d₆) ppm 2.90 (dd, 2H, J=5.6, 15.9 Hz), 3.40(shielded by H₂O peak in DMSO-d₆, 2H), 3.89 (s, 3H), 4.96 (m, 1H), 6.86(dd, 1H, J=2.5, 8.8 Hz), 6.98 (d, 1H, J=2.5 Hz), 7.17 (m, 2H), 7.28 (m,2H), 7.74 (d, 1H, J=8.8 Hz), 8.55 (br, 1H), 8.64 (s 1H). LC/MS: m/z 335(M+1)⁺, 333 (M−1)⁻.

Example 87-methoxy-2-(3-morpholin-4-yl-propylamino)-quinoline-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) ppm 1.80 (quintet, 2H, J=6.8 Hz), 2.46 (m,6H), 3.57 (t, 2H, J=6.8 Hz), 3.62 (t, 4H, J=4.5 Hz), 3.87 (s, 3H), 6.83(dd, 1H, J=2.2, 8.8 Hz), 6.90 (d, 1H, J=2.2 Hz), 7.69 (d, 1H, J=8.8 Hz),8.60 (s 1H). LC/MS: m/z 346 (M+1)⁺, 344 (M−1)⁻.

Additional compounds of formula (I) having a phenethyl, benzyl,heterocyclyl, cycloalkyl, alkylamine, or heteroaryl R² substituent wereprepared according to the procedures of Schemes 1 and 3 and werecharacterized as being the following.

-   7-methoxy-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-quinoline-3-carboxylic    acid;-   2-(4-tert-butyl-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-quinoline-3-carboxylic    acid;-   2-(4-dimethylamino-benzylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-(2-morpholin-4-yl-ethylamino)-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(4-phenoxy-phenyl)-ethylamino]-quinoline-3-carboxylic    acid;-   2-cyclohexylamino-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-quinoline-3-carboxylic    acid; 2-(2-hydroxy-ethylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(2-hydroxy-2-phenyl-ethylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-[2-(3-bromo-4-methoxy-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-(4-methyl-benzylamino)-quinoline-3-carboxylic acid;-   7-methoxy-2-(2-pyridin-3-yl-ethylamino)-quinoline-3-carboxylic acid;-   2-[2-(3,4-dimethoxy-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-benzylamino-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-[2-(4-methoxy-phenyl)-ethylamino]-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(2-methoxy-phenyl)-ethylamino]-quinoline-3-carboxylic    acid;-   7-methoxy-2-(4-methoxy-benzylamino)-quinoline-3-carboxylic acid;-   2-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-(3-trifluoromethyl-benzylamino)-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(4-nitro-phenyl)-ethylamino]-quinoline-3-carboxylic    acid;-   2-(3-imidazol-1-yl-propylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-(4-sulfamoyl-benzylamino)-quinoline-3-carboxylic acid;-   7-methoxy-2-(3-methoxy-benzylamino)-quinoline-3-carboxylic acid;-   2-(2-chloro-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-[2-(3-fluoro-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-[2-(4-amino-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-(3-amino-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(2-benzo[1,3]dioxol-5-yl-ethylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(3-methoxy-phenyl)-ethylamino]-quinoline-3-carboxylic    acid;-   2-[2-(3-chloro-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(4-sulfamoyl-phenyl)-ethylamino]-quinoline-3-carboxylic    acid;-   2-[2-(2-chloro-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-[2-(4-hydroxy-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-(3-bromo-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(3-chloro-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-(2-piperazin-1-yl-ethylamino)-quinoline-3-carboxylic    acid;-   7-methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-quinoline-3-carboxylic    acid HCl;-   7-methoxy-2-(3-morpholin-4-yl-propylamino)-quinoline-3-carboxylic    acid; and-   7-methoxy-2-piperidin-1-yl-quinoline-3-carboxylic acid;-   7-methoxy-2-(3-pentafluorosulfanyl-phenylamino)-quinoline-3-carboxylic    acid;-   7-methoxy-2-(5,6,7,8-tetrahydro-naphthalen-1-ylamino)-quinoline-3-carboxylic    acid;-   7-methoxy-2-(naphthalen-1-ylamino)-quinoline-3-carboxylic acid;-   2-[4-(2-diethylamino-ethylcarbamoyl)-phenylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   2-(3-tert-butoxycarbonylamino-benzylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(4-tert-butoxycarbonylamino-benzylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(4-amino-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-(2,4,6-trimethoxy-benzylamino)-quinoline-3-carboxylic    acid;-   7-methoxy-2-[3-(3-phenyl-ureido)-benzylamino]-quinoline-3-carboxylic    acid;-   7-methoxy-2-[4-(3-phenyl-ureido)-benzylamino]-quinoline-3-carboxylic    acid;-   7-methoxy-2-[4-(toluene-4-sulfonylamino)-benzylamino]-quinoline-3-carboxylic    acid;-   2-(4-chloro-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(4-carboxy-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(4-hydroxy-piperidin-1-yl)-7-methoxy-quinoline-3-carboxylic acid;-   2-(3-diethylamino-propylamino)-7-methoxy-quinoline-3-carboxylic acid    HCl.-   2-(3-dimethylamino-propylamino)-7-methoxy-quinoline-3-carboxylic    acid HCl;-   2-(2-dimethylamino-ethylamino)-7-methoxy-quinoline-3-carboxylic acid    HCl;-   7-methoxy-2-(3-ureido-benzylamino)-quinoline-3-carboxylic acid; and-   2-(dimethylaminosulfonylamino-benzylamino)-7-methoxy-quinoline-3-carboxylic    acid.

Additional methods for preparing compounds of formula (I) wherein R² isan aryl or alkyl group and R³ is as defined above are depicted inSchemes 4-6 and are specifically discussed in International ApplicationPCT/US02/10657 on pages 17-19.

In general, the synthetic methods used herein are those detailed in J.C. S. Perkin 1, 1981, 5, 1520-30 and J. Het. Chem. 1991, 28(5), 1339-40for preparing substituted carboxy quinolines. Briefly, a substitutedaniline (I) is acylated with acetic anhydride in pyridine to give theresulting acetanilide (II). Treatment of the acetanilide (II) with POCl₃in DMF gives a 2-chloride-3-formyl quinoline (III). Oxidation with AgNO₃in basic ethanol gives the corresponding 2-chloride-3-carboxy quinoline(IV). The 2-chloro can be replaced with an appropriate amines in DMSO togive the resulting 2-substituted quinoline (V) (Scheme 1).

Alternatively, the method of Scheme 5 may be used, in which the2-chloride-3-carboxy quinoline (IV) is treated with an aryl amine in thepresence of excess of lithium hexamethyldisilazane in THF (−70 C to RT)to give the 2-substituted quinoline (V) (Scheme 2). For alkyl amines,excess of the lithium salt of the particular alkyl amine is used inplace of lithium hexamethyldisilazane.

Additional compounds of formula (I) having an alkyl, aryl, or otherappropriate R² substituent were prepared according to the procedures ofSchemes 4 and 5 and were characterized as the following.

-   2-(tert-butoxycarbonylmethyl-amino)    -7-methoxy-quinoline-3-carboxylic acid;-   2-[2-(2-hydroxy-ethoxy)-ethylamino]-7-methoxy-quinoline-3-carboxylic    acid;-   7-methoxy-2-(3-methoxy-propylamino)-quinoline-3-carboxylic acid;-   7-methoxy-2-(2-methoxy-ethylamino)-quinoline-3-carboxylic acid;-   2-(3-hydroxy-propylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(2-carboxy-ethylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-propylamino-quinoline-3-carboxylic acid;-   2-(carboxymethyl-amino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(3,4-dichlorophenylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(3-biphenylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-(phenylamino)-quinoline-3-carboxylic acid;-   7-methoxy-2-(methyl-3-methylphenylamino)-quinoline-3-carboxylic    acid;-   2-(cyclohexylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(3-chlorophenylamino)-6,7-dimethoxy-quinoline-3-carboxylic acid;-   2-(3-chlorophenylamino)-6,7-methylenedioxy-quinoline-3-carboxylic    acid;-   2-(3-chlorophenylamino)-7-hydroxy-quinoline-3-carboxylic acid;-   8-bromo-2-(3-chlorophenylamino)-7-hydroxy-quinoline-3-carboxylic    acid;-   2-(3-chlorophenylamino)-7-methoxy-quinoline-3-carboxamide    phenylsulphonamide;-   2-(3-chlorophenylamino)-7-methoxy-quinoline-3-carboxamide    2-nitro-phenylsulphonamide;-   2-(3-chlorophenylamino)-7-methoxy-quinoline-3-carboxamide    methylsulphonamide;-   8-bromo-2-(3-chlorophenylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(3-acetophenylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(2-benzophenone-yl-amino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(2-fluoro-5-methylphenylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(2-cyanophenylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(2-chloro-6-methylphenylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(4-carboxybenzylamino)-7-methoxy-quinoline-3-carboxylic acid;-   2-(3-chloro-6-methoxyphenylamino)-7-methoxy-quinoline-3-carboxylic    acid;-   2-(2-ethylphenylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-(4-nitrophenylamino)-quinoline-3-carboxylic acid;-   2-(4-carboxamidophenylamino)-7-methoxy-quinoline-3-carboxylic acid;-   7-methoxy-2-(4-hydroxyphenethylamino)-quinoline-3-carboxylic acid;    and-   7-methoxy-2-(piperidin-4-ol)-quinoline-3-carboxylic acid.

Compounds of Formula (I) having a substituted aryl substituent atposition R² as well as phenyl amide derivatives thereof may be preparedaccording to the procedures of Scheme 7 and Examples 9-12.

Example 9 3-(2-Chloro-phenylamino)-6-methoxy-naphthalene-2-carboxylicacid

This compound has been prepared in 76% yield via the method exemplifiedin the first step of Scheme 7.

Example 10 2-(2-Chloro-phenylamino)-7-methoxy-quinoline-3-carboxylicacid phenylamide

EDC (633 mg, 3.3 mmol) was added to a solution of2-(2-Chloro-phenylamino)-7-methoxy-quinoline-3-carboxylic acid (986 mg,3.0 mmol), HOBt (446 mg, 3.3 mmol) and aniline (307 mg, 3.3 mmol) in DMF(5 ml) at room temperature. After stirring the mixture for 1 hr, CH₂Cl₂was used to extract the reaction mixture, and washed with water,saturated brine and then dried with magnesium sulfate. The solvent wasremoved under reduced pressure to give yellow oil. The yellow oil waspurified by chromatography on SCX column using MeOH as eluent. At last,2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acidphenylamide was obtained as yellow solid after recrystallization fromCH₂Cl₂ and Hexane; 947 mg (78%).

Example 11 2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylicacid phenylamide

2-(2-Chloro-phenylamino)-7-methoxy-quinoline-3-carboxylic acidphenylamide (404 mg, 1.0 mmol) was dissolved in dry CH₂Cl₂ (5 ml). Aftercooling to −78° C., 1.0 N BBr3 (5.0 ml, 5.0 mmol) in CH₂Cl₂ was droppedinto the above solution over 5 min. The reaction mixture was allowed towarm to room temperature over 1 hr and stirred for 5 days. CH₂Cl₂ wasadded to extract the reaction mixture, and washed with water, saturatedbrine and then dried with magnesium sulfate. After evaporating thesolvent under reduced pressure, the residue was purified bychromatography on SCX column using MeOH as eluent. At last,2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acidphenylamide was obtained as yellow solid after recrystallization fromCH₂Cl₂ and Hexane; 210 mg (54%).

Example 12 2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylicacid

A suspension of2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acidphenylamide (17 mg, 0.04 mmol) in 16N aqueous HCl (0.1 ml) and1,4-Dioxane (0.1 ml) was heated at reflux for 5 days. After evaporatingthe solvent, the residue was recrystallized from methanol to give2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acid as thewhite crystal; 13 mg (990%). ¹H NMR (400 MHz, DMSO-d₆) ppm 6.96 (dd, 1H,J=2.3, 8.6 Hz), 6.99 (d, 1H. J=2.3 Hz), 7.04 (ddd, 1H, J=1.5, 7.8, 8.8Hz), 7.40 (ddd, 1H, J=1.5, 7.8, 8.8 Hz), 7.52 (dd, 1H, J=1.5, 7.8 Hz),7.83 (d, 1H, J=8.8 Hz), 8.84 (s, 1H), 9.10 (d, 1H, J=11.2 Hz), 10.48 (s,1H), 11.05 (s, 1H). LC/MS: m/z 315 (M+1)⁺, 313 (M−1)⁻.

Additional compounds of formula (I) were prepared according to theprocedures of Scheme 7 and were characterized as being the following.

-   2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acid; and-   2-(2-Chloro-phenylamino)-7-(2-hydroxy-ethoxy)-quinoline-3-carboxylic    acid.

Further additional compounds of formula (I) were prepared according tothe procedures of Scheme 1, 2, 3, 4, 5, 6, and/or 7 as appropriate andwere characterized as being the following:

Biological Data YAK3 Scintillation Proximity Assays Using Ser164 ofMyelin Basic Protein as the Phosphoacceptor

Source of Ser164 Substrate Peptide:

The biotinylated Ser164, S164A peptide(Biotinyl -LGGRDSRAGS*PMARR—OH),sequence derived from the C-terminus of bovine myelin basic protein(MBP) with Ser162 substituted as Ala162, was purchased from CaliforniaPeptide Research Inc. (Napa, Calif.), and its purity was determined byHPLC. Phosphorylation occurs at position 164 (marked S* above). Thecalculated molecular mass of the peptide was 2166 dalton. Solid samplewas dissolved at 10 mM in DMSO, aliquoted, and stored at −20° C. untiluse.

Source of Enzyme:

hYAK3: Glutathione-S-Transferase (GST)-hYak3-His6 containing amino acidresidues 124-526 of human YAK3 was purified from baculovirus expressionsystem in Sf9 cells using Glutathione Sepharose 4B column chromatographyfollowed by Ni-NTA-Agarose column chromatography. Purity greater than65% typically was achieved. Samples, in 50 mM Tris, 150 mM NaCl, 10%glycerol, 0.1% Triton, 250 mM imidazole, 10 mM β-mercapto ethanol, pH8.0.

were stored at −80° C. until use.

Kinase assay of purified hYAK3:

Assays were performed in 96 well (Costar, Catalog No. 3789) or 384 wellplates (Costar, Catalog No. 3705). Reaction (in 20, 25, or 40 μl volume)mix contained in final concentrations 25 mM Hepes buffer, pH 7.4; 10 mMMgCl₂; 10 mM β-mercapto ethanol; 0.0025% Tween-20; 0.001 mM ATP, 0.1

Ci of [

-³³P]ATP; purified hYAK3 (7-14 ng/assay; 4 nM final); and 4 μM Ser164peptide. Compounds, titrated in DMSO, were evaluated at concentrationsranging from 50 μM to 0.5 nM. Final assay concentrations of DMSO did notexceed 5%, resulting in less than 15% loss of YAK3 activity relative tocontrols without DMSO. Reactions were incubated for 2 hours at roomtemperature and were stopped by a 75 ul addition of 0.19 μg StreptavidinScintillation Proximity beads (Amersham Pharmacia Biotech, Catalog No.RPNQ 0007) in PBS, pH 7.4, 10 mM EDTA, 0.1% Triton X-100, 1 mM ATP.Under the assay conditions defined above, the K_(m)(apparent) for ATPwas determined to be 7.2+/−2.4 μM. Assay results are depicted in TableI. TABLE I Ex. No YAK3 1 ++ 2 +++ 3 +++ 4 +++ 5 +++ 6 +++ 7 +++ 8 ++ 12++++ = pIC₅₀ of 4.0-5.0;++ = pIC₅₀ of 5.0-6.0;+++ = pIC₅₀ of >6.0;

1. A compound of Formula (I):

wherein: R¹ is —H or C₁-C₆ alkyl; R² is the group defined by-(Q)_(q)-(Q¹)_(r)-(Q²), wherein: Q is CH₂ and q is 0, 1, 2, 3, or 4; Q¹is O, NH, or C(H)(R′) where R′ is —OH; and r is 0 or 1, and Q² is —H,C₁-C₆ alkyl, aryl, heterocyclic, C₃-C₇ cycloalkyl, —C(O)OR^(b),NR^(b)R^(b), or heteroaryl; where Q² is optionally substituted with atleast one R^(a) group; R³ and R^(3a) are independently selected from —H,C₁-C₆ alkyl, or C₁-C₆ hydroxyalkyl, m is 0 or 1, and n is 0 or 1, or mis 1 and n is 1 and R³ and R^(3a) together with the atoms to which theyare attached form the optionally substituted fused ring

R⁴ is —OH, —NHS(O)₂R^(c), or —N(R^(b))R; R⁵ is —H or halo; R is —H,aryl, —OR^(b); R^(a) is independently selected from C₁-C₆ alkyl, halo,aryl, —C(O)OR^(b), —C(O)R^(d), —OH, —NR^(b)R^(b), —N(H)C(O)OR^(b),—N(H)C(O)N(H)R^(e), —N(H)S(O)₂R^(c), —N(H)S(O)₂NR^(b)R^(b), C₁-C₆alkoxy, C₁-C₆ haloalkyl, —NO₂, —CN, —SF₅, ═O, —S(O)₂NR^(b)R^(b), oraryloxy; R^(b) is —H, C₁-C₆ alkyl, or C₂-C₄ alkenyl; R^(c) is aryl orC₁-C₆ alkyl; R^(d) is C₁-C₆alkyl, aryl, NR^(b)R^(b), orN(H)(CH₂)_(n)NR^(b)R^(b), R^(e) is —H, aryl or C₁-C₆ alkyl; s is 1, 2,3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
 2. Acompound as claimed in claim 1, selected from the group consisting of:2-(3-tert-butoxycarbonylamino-propylamino)-7-methoxy-quinoline-3-carboxylicacid; 2-(3-amino-propylamino)-7-methoxy-quinoline-3-carboxylic acid;2-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-ethylamino]-7-methoxy-quinoline-3-carboxylicacid; 2-(4-tert-butoxycarbonylamino-butylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(2-tert-butoxycarbonylamino-ethylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(3-dimethylamino-propylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(2-dimethylamino-ethylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(2-amino-ethylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(4-amino-butylamino)-7-methoxy-quinoline-3-carboxylic acid;2-benzylamino-7-methoxy-quinoline-3-carboxylic acid;7-methoxy-2-phenethylamino-quinoline-3-carboxylic acid;7-methoxy-2-(2-pyridin-4-yl-ethylamino)-quinoline-3-carboxylic acid;2-(2-dimethylamino-ethylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(indan-2-ylamino)-7-methoxy-quinoline-3-carboxylic acid;7-methoxy-2-(3-morpholin-4-yl-propylamino)-quinoline-3-carboxylic acid;2-(3-diethylamino-propylamino)-7-methoxy-quinoline-3-carboxylic acid;7-methoxy-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-quinoline-3-carboxylicacid; 2-(4-tert-butyl-benzylamino)-7-methoxy-quinoline-3-carboxylicacid;7-methoxy-2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-quinoline-3-carboxylicacid; 2-(4-dimethylamino-benzylamino)-7-methoxy-quinoline-3-carboxylicacid; 7-methoxy-2-(2-morpholin-4-yl-ethylamino)-quinoline-3-carboxylicacid;7-methoxy-2-[2-(4-phenoxy-phenyl)-ethylamino]-quinoline-3-carboxylicacid; 2-cyclohexylamino-7-methoxy-quinoline-3-carboxylic acid;7-methoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-quinoline-3-carboxylicacid; 2-(2-hydroxy-ethylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(2-hydroxy-2-phenyl-ethylamino)-7-methoxy-quinoline-3-carboxylic acid;2-[2-(3-bromo-4-methoxy-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylicacid; 7-methoxy-2-(4-methyl-benzylamino)-quinoline-3-carboxylic acid;7-methoxy-2-(2-pyridin-3-yl-ethylamino)-quinoline-3-carboxylic acid;2-[2-(3,4-dimethoxy-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylicacid; 2-benzylamino-7-methoxy-quinoline-3-carboxylic acid;7-methoxy-2-(3-morpholin-4-yl-propylamino)-quinoline-3-carboxylic acid;and 7-methoxy-2-piperidin-1-yl-quinoline-3-carboxylic acid;7-methoxy-2-(3-pentafluorosulfanyl-phenylamino)-quinoline-3-carboxylicacid;7-methoxy-2-(5,6,7,8-tetrahydro-naphthalen-1-ylamino)-quinoline-3-carboxylicacid; 7-methoxy-2-(naphthalen-1-ylamino)-quinoline-3-carboxylic acid;2-[4-(2-diethylamino-ethylcarbamoyl)-phenylamino]-7-methoxy-quinoline-3-carboxylicacid;2-(3-tert-butoxycarbonylamino-benzylamino)-7-methoxy-quinoline-3-carboxylicacid;2-(4-tert-butoxycarbonylamino-benzylamino)-7-methoxy-quinoline-3-carboxylicacid; 2-(4-amino-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;7-methoxy-2-(2,4,6-trimethoxy-benzylamino)-quinoline-3-carboxylic acid;7-methoxy-2-[3-(3-phenyl-ureido)-benzylamino]-quinoline-3-carboxylicacid;7-methoxy-2-[4-(3-phenyl-ureido)-benzylamino]-quinoline-3-carboxylicacid;7-methoxy-2-[4-(toluene-4-sulfonylamino)-benzylamino]-quinoline-3-carboxylicacid; 7-methoxy-2-(3-ureido-benzylamino)-quinoline-3-carboxylic acid;2-(dimethylaminosulfonylamino-benzylamino)-7-methoxy-quinoline-3-carboxylicacid;7-methoxy-2-[2-(4-methoxy-phenyl)-ethylamino]-quinoline-3-carboxylicacid;7-methoxy-2-[2-(2-methoxy-phenyl)-ethylamino]-quinoline-3-carboxylicacid; 7-methoxy-2-(4-methoxy-benzylamino)-quinoline-3-carboxylic acid;2-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-7-methoxy-quinoline-3-carboxylicacid; 7-methoxy-2-(3-trifluoromethyl-benzylamino)-quinoline-3-carboxylicacid; 7-methoxy-2-[2-(4-nitro-phenyl)-ethylamino]-quinoline-3-carboxylicacid; 2-(3-imidazol-1-yl-propylamino)-7-methoxy-quinoline-3-carboxylicacid; 7-methoxy-2-(4-sulfamoyl-benzylamino)-quinoline-3-carboxylic acid;7-methoxy-2-(3-methoxy-benzylamino)-quinoline-3-carboxylic acid;2-(2-chloro-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;2-[2-(3-fluoro-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylicacid; 2-[2-(4-amino-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylicacid; 2-(3-amino-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(2-benzo[1,3]dioxol-5-yl-ethylamino)-7-methoxy-quinoline-3-carboxylicacid;7-methoxy-2-[2-(3-methoxy-phenyl)-ethylamino]-quinoline-3-carboxylicacid;2-[2-(3-chloro-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylicacid;7-methoxy-2-[2-(4-sulfamoyl-phenyl)-ethylamino]-quinoline-3-carboxylicacid;2-[2-(2-chloro-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylicacid;2-[2-(4-hydroxy-phenyl)-ethylamino]-7-methoxy-quinoline-3-carboxylicacid; 2-(3-bromo-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(3-chloro-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;7-methoxy-2-(2-piperazin-1-yl-ethylamino)-quinoline-3-carboxylic acid;7-methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-quinoline-3-carboxylicacid; 7-methoxy-2-piperidin-1-yl-quinoline-3-carboxylic acid;2-(4-chloro-benzylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(4-hydroxy-piperidin-1-yl)-7-methoxy-quinoline-3-carboxylic acid;2-(tert-butoxycarbonylmethyl-amino) -7-methoxy-quinoline-3-carboxylicacid;2-[2-(2-hydroxy-ethoxy)-ethylamino]-7-methoxy-quinoline-3-carboxylicacid; 7-methoxy-2-(3-methoxy-propylamino)-quinoline-3-carboxylic acid;7-methoxy-2-(2-methoxy-ethylamino)-quinoline-3-carboxylic acid;2-(3-hydroxy-propylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(2-carboxy-ethylamino)-7-methoxy-quinoline-3-carboxylic acid;7-methoxy-2-propylamino-quinoline-3-carboxylic acid;2-(carboxymethyl-amino)-7-methoxy-quinoline-3-carboxylic acid;3-(2-chloro-phenylamino)-6-methoxy-naphthalene-2-carboxylic acid;2-(2-chloro-phenylamino)-7-methoxy-quinoline-3-carboxylic acidphenylamide; 2-(2-chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylicacid phenylamide;2-(2-chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acid;2-(2-chloro-phenylamino)-7-(2-hydroxy-ethoxy)-quinoline-3-carboxylicacid; 2-(3,4-dichlorophenylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(3-biphenylamino)-7-methoxy-quinoline-3-carboxylic acid;7-methoxy-2-(phenylamino)-quinoline-3-carboxylic acid;7-methoxy-2-(methyl-3-methylphenylamino)-quinoline-3-carboxylic acid;2-(cyclohexylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(3-chlorophenylamino)-6,7-dimethoxy-quinoline-3-carboxylic acid;2-(3-chlorophenylamino]-6,7-methylenedioxy-quinoline-3-carboxylic acid;2-(3-chlorophenylamino)-7-hydroxy-quinoline-3-carboxylic acid;8-bromo-2-(3-chlorophenylamino)-7-hydroxy-quinoline-3-carboxylic acid;2-(3-chlorophenylamino)-7-methoxy-quinoline-3-carboxamidephenylsulphonamide;2-(3-chlorophenylamino)-7-methoxy-quinoline-3-carboxamide2-nitro-phenylsulphonamide;2-(3-chlorophenylamino)-7-methoxy-quinoline-3-carboxamidemethylsulphonamide;8-bromo-2-(3-chlorophenylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(3-acetophenylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(2-benzophenone-yl-amino)-7-methoxy-quinoline-3-carboxylic acid;2-(2-fluoro-5-methylphenylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(2-cyanophenylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(2-chloro-6-methylphenylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(4-carboxybenzylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(3-chloro-6-methoxyphenylamino)-7-methoxy-quinoline-3-carboxylic acid;2-(2-ethylphenylamino)-7-methoxy-quinoline-3-carboxylic acid;7-methoxy-2-(4-nitrophenylamino)-quinoline-3-carboxylic acid;2-(4-carboxamidophenylamino)-7-methoxy-quinoline-3-carboxylic acid;7-methoxy-2-(4-hydroxyphenethylamino)-quinoline-3-carboxylic acid; and7-methoxy-2-(piperidin-4-ol)-quinoline-3-carboxylic acid; or a salt,solvate, or physiologically functional derivative thereof.
 3. A compoundas claimed in claim 1, selected from the group consisting of:

or a salt, solvate, or physiologically functional derivative thereof. 4.A pharmaceutical composition, comprising: a therapeutically effectiveamount of a compound as claimed in claim 1, or a salt, solvate, or aphysiologically functional derivative thereof and one or more ofpharmaceutically acceptable carriers, diluents and excipients.
 5. Amethod of treating a disorder in a mammal, said disorder being mediatedby inappropriate YAK3 activity, comprising: administering to said mammala therapeutically effective amount of a compound as claimed in claim 1,or a salt, solvate, or a physiologically functional derivative thereof.6-7. (canceled)
 8. A compound as claimed in claim 1, wherein R¹ is —H ormethyl.
 9. A compound as claimed in claim 1, wherein R¹ is —H.
 10. Acompound as claimed in claim 1, wherein q and r are 0, and R² is -(Q²).11. A compound as claimed in claim 1, wherein q is 1, 2, 3, or 4, r is 0and R² is -(Q)_(q)— (Q²).
 12. A compound as claimed in claim 1, whereinq is 0, r is 1, and R² is -(Q¹)-(Q²).
 13. A compound as claimed in claim1, wherein q is 1, 2, 3, or 4 and r are 1, and R² is -(Q)_(q)-(Q¹)-(Q²).14. A compound as claimed in claim 1, wherein q is 1, 2, 3, or 4 and Qis CH₂.
 15. A compound as claimed in claim 1, wherein q is 1, 2, or 3and Q is CH₂.
 16. A compound as claimed in claim 1, wherein q is 1 or 2and Q is CH₂.
 17. A compound as claimed in claim 1, wherein r is 0 or 1and Q¹ is NH or O.
 18. A compound as claimed in claim 1, wherein r is 0or 1 and Q¹ is NH.
 19. A compound as claimed in claim 1, wherein r is 0.20. A compound as claimed in claim 1, wherein Q² is C₁-C₆ alkyl, aryl,heterocyclic, C₃-C₇cycloalkyl, or heteroaryl each optionally substitutedwith at least one R^(a) group.
 21. A compound as claimed in claim 1,wherein Q² is aryl optionally substituted with at least one R^(a) group.22. A compound as claimed in claim 1, wherein Q is CH², q is 1, 2, 3, or4, r is 0, and Q² is aryl optionally substituted with at least one R^(a)group.
 23. A compound as claimed in claim 1, wherein Q is CH², q is 1,2, or 3, r is 0, and Q² is phenyl optionally substituted with at leastone R^(a) group.
 24. A compound as claimed in claim 1, wherein Q is CH²,q is 2, r is 0, and Q² is phenyl optionally substituted with at leastone R^(a) group.
 25. A compound as claimed in claim 1, wherein q is 0, ris 0, and Q² is aryl optionally substituted with at least one R^(a)group.
 26. A compound as claimed in claim 1, wherein q is 0, r is 0, andQ² is phenyl optionally substituted with at least one R^(a) group.
 27. Acompound as claimed in claim 1, wherein q is 0, r is 0, and Q² is C₁-C₆alkyl optionally substituted with at least one R^(a) group.
 28. Acompound as claimed in claim 1, wherein m is 0, n is 1, and R³ is —H orC₁-C₆ alkyl.
 29. A compound as claimed in claim 1, wherein m is 0, n is1, and R³ is —H or methyl.
 30. A compound as claimed in claim 1, whereinm is 1, n is 0, and R^(3a) is —H or C₁-C₆ alkyl.
 31. A compound asclaimed in claim 1, wherein m is 1, n is 0, and R^(3a) is —H or methyl.32. A compound as claimed in claim 1, wherein m is 1 and n is 1 and R³and R^(3a) together with the atoms to which they are attached form theoptionally substituted fused ring


33. A compound as claimed in claim 1, wherein R⁴ is —NHS(O)₂R^(c),wherein R^(c) is aryl or C₁-C₆ alkyl.
 34. A compound as claimed in claim1, wherein R^(c) is phenyl, substituted phenyl or methyl.
 35. A compoundas claimed in claim 1, wherein R⁴ is —OH.
 36. A compound as claimed inclaim 1, wherein R⁴ is —N(R^(b))R wherein R is —H, aryl or —OR^(b) andR^(b) is —H, C₁-C₆ alkyl, or C₁-C₆ alkenyl.
 37. A compound as claimed inclaim 1, wherein R⁵ is halo.
 38. A compound as claimed in claim 1,wherein R⁵ is —Br.
 39. A compound as claimed in claim 1, wherein R⁵ is—H.